Glutamate Oxaloacetate Transaminase Nanoparticles targeted to the Brain for Neuroprotection in Ischemic Stroke (GOTTARG)

The project will develop and test the first targeted and long-acting nanomedicine with neuroprotective properties for ischemic stroke, with potential application in other neurological diseases.

The Team will demonstrate that the targeted delivery of a long-acting glutamate oxaloacetate transaminase (GOT) nanoparticle to the brain in order to enhance the neuroprotective character of GOT (i.e., prevention of neuronal apoptosis and cell death) in a model ischemic stroke. Systemically administered GOT has been demonstrated to deplete blood glutamate levels, which in turn causes an efflux of excess glutamate from the brain.

One major shortcoming of this approach is that the systemic effect of GOT on brain glutamate concentration is short-lived (~1 h), mainly because of its rapid elimination from the body. The project will: i) increase the circulatory half-life of GOT and ii) target GOT to- or near to- the ischemic region of the brain where GOT can exert its therapeutic catalytic activity. These objectives will be met by preparing a Blood-Brain-Barrier (BBB)-targeted nano-formulation of GOT (GOT-NP).

What is particularly original in this strategy is that accumulation of GOT-NP at the blood-side of the BBB will promote the efflux of glutamate from the brain by increasing the glutamate gradient on either side of the BBB. As such, GOT-NP does not actually have to cross the BBB to produce an enhanced neuroprotective effect. Crossing the BBB, which is substantially more challenging, would represent an added bonus of selectively depleting glutamate in the cerebrospinal fluid.

In addition to the design and synthesis of GOT-NP, this project will investigate and validate iii) the mechanism of in vitro neuroprotection as well as iv) the in vivo biodistribution and neuroprotective effect of GOT-NP in an animal model of ischemic stroke, in order to conclude pre-clinical studies and place the Team in a position to embark on clinical testing.